Hindawi BioMed Research International Volume 2018, Article ID 8718053, 7 pages https://doi.org/10.1155/2018/8718053

Review Article D-Tagatose Is a Promising Sweetener to Control Glycaemia: A New Functional Food

Marion Guerrero-Wyss ,1 Samuel Durán Agüero ,1 and Lisse Angarita Dávila2

1 Escuela de Nutricion,FacultadCienciasDeLaSal´ ud, Universidad San Sebastian,´ Santiago, Chile 2Carrera de Nutricion,FacultaddeMedicina,UniversidadAndresBello,SedeConcepci´ on,´ Talcahuano, Chile

Correspondence should be addressed to Marion Guerrero-Wyss; [email protected]

Received 27 June 2017; Revised 9 November 2017; Accepted 13 December 2017; Published 9 January 2018

Academic Editor: Konstantinos Papatheodorou

Copyright © 2018 Marion Guerrero-Wyss et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Te objective of the current research was to review and update evidence on the dietary efect of the consumption of tagatose in , as well as to elucidate the current approach that exists on its production and biotechnological utility in functional food for diabetics. Articles published before July 1, 2017, were included in the databases PubMed, EBSCO, Google Scholar, and Scielo, including the terms “Tagatose”, “Sweeteners”, “Diabetes Mellitus type 2”, “Sweeteners”, “D-Tag”. D-Tagatose (D-tag) is an of which is approximately 90% sweeter than . Preliminary studies in animals and preclinical studies showed that D-tag decreased levels, which generated great interest in the scientifc community. Recent studies indicate that tagatose has low , a potent hypoglycemic efect, and eventually could be associated with important benefts for the treatment of obesity. Te authors concluded that D-tag is promising as a sweetener without major adverse efects observed in these clinical studies.

1. Introduction great interest in the scientifc community [5]. Te pro- posed action mechanism may involve interference in the D-Tagatose (D-tag) is an isomer of fructose which is approx- absorption of through inhibition of intestinal imately 90% sweeter than sucrose. Fructose that corresponds disaccharidases and glucose transportation. It can also act toanaturalhexosewasdevelopedasalow-caloriesugar through the inhibition of hepatic glycogenolysis [1]. In substitute. addition to presenting an efect in the reduction of total Only 20% of the orally ingested tagatose is metabolized cholesterol, VLDL, and LDL compared with sucrose [6], completely and mainly in the liver [1]. In 2001, D-tag was likewise D-tag has contributed to increasing levels of HDL appointed by the Food and Drug Administration (FDA) as a cholesterol [7]. generally recognized safe product (GRAS), and subsequently Te D-tag would have an antihyperglycemic potential it has been used as a nutritional sweetener or low in calories through its benefcial efects on the increment of postprandial [2]. Afer this, the European Union (EU) introduced D-tag serum glucose and hyperinsulinemia. Recent studies indicate as a “new food ingredient,” without any restrictions on the that tagatose has a powerful antidiabetic efect and could amount to be used [1, 2]. eventually be associated with important benefts for the Currently, D-tag is used as a sweetener in beverages, treatment of obesity. However, preliminary results of a study yogurt, creams, and dietetic candy [3]. indicated that there were not any changes in glucose or A method for the mature production of D-tag is the direct levels afer oral administration of D-tag while fasting isomerization of G- in D-tag, with metal hydroxides [8]. such as chemical catalysts in basic conditions [4]. Teobjectiveofthisresearchistoreviewandupdate Preliminary animal studies and preclinical studies evidence about the therapeutic efect of the consumption showed that D-tag decreased glucose levels, generating of tagatose in patients with diabetes type 2 as well as to 2 BioMed Research International

Table 1: Antihyperglycemic efect of D-tagatose.

Mechanism described or Sample population Methodology Findings proposed Te glucose area under the curve (AUC) was reduced signifcantly also D-Tagatose directly inhibits Tey were given 75 g of glucose, 75 g of by pretreatment with D-tag in a Normal subjects and theabsorptionofglucose D-tag, or 75 g of D-tag 30 min prior to dose-dependent manner in patients type 2 diabetics patients. by intestinal a 75 g oral glucose tolerance test. with diabetes mellitus (� < 0.05 for disaccharidases. 10 g D-tag, � < 0.001for20gD-tag, and � = 0.0001 for 30 g D-tag) [8]. Tey were given D-tag in three treatment groups: 2.5 g, 5.0 g, and 7.5 g Only the 7.5g dosage group exhibited Inhibition of sucrose given orally (three times daily, reductions of fasting glucose from Type 2 diabetics patients. activity by D-tag has been immediately prior to meals). Eight baseline at the 3- and 6-month time in rabbit small intestine. weeks afer screening and stabilization points [1]. of diabetics. D-Tagatose signifcantly reduced Unlike many other diabetes HbA1c compared to placebo. Two randomized groups were given a drugs, the longer the D-Tagatose was efective at reducing dose of D-tag (15 g) and the other D-tagatose therapy, the the HbA1c level when administered for Type 2 diabetics patients. group was given a dose of placebo better the efcacy, since the two months at doses of 15 g TID. (1.5 g), which were dissolved in 125 to intestinal mucosa will be Also signifcant reductions in the 250 ml of water three times a day (TD). exposed for a longer period HbA1c level at six and ten months to D-tag. were also met [9]. elucidate the current approach that exists on its production beverage with tagatose (5 g), only hyperglycemic individuals and biotechnological use in functional food for diabetics. had a signifcant reduction of blood glucose at 120 min (� = 0.019), as well as in the blood glucose area under 2. Methodology the curve (AUC) (� = 0.017)[1].Normalindividualswho received a high dose of the beverage with tagatose (10 g) Articles published before July 1, 2017, were selected for the showed decreased levels of serum insulin, AUC of insulin, completion of this review; the search was carried out in and C-peptide. Terefore, these results suggest that a bever- thedatabasesPubMed,EBSCO,GoogleScholar,andScielo, age sweetened with tagatose could control the postprandial including terms or key words “Tagatose”, “Sweeteners”, “Dia- glycemic response in individuals with hyperglycemia [1]. betes Mellitus type 2”, “Sweeteners”, “D-Tag”. Another study [11] was performed to investigate acute Tis review included clinical interventions in animals and efects on blood levels in 8 healthy individuals and in humans, as well as studies on the formulation and production 8 individuals with DM 2, afer the oral intake of 75 g of D- offoodthatcontaintagatose.TesearchincludedEnglishand tagatose (D-tag) alone and combined with 75 g of glucose. Spanish as languages. Diabetics received separately and at 0, 10, 15, 20, and 30 min 75gofD-tag,30minutesbeforeadoseof75gofglucose. 3. Tagatose and Blood Glucose Oral load with D-tag did not alter blood sugar levels or insulininanygroup.Tepretreatmentwith75gofD-tag A phase II study with more than 6 months of duration and attenuated the glycemic curve in diabetics [11], signifcantly a phase III efectiveness study with more than 12 months of reducingthebloodglucoseareaunderthecurve(AUC) duration used D-tag to reduce HbA1c in 161 and 494 diabetic and the glycemic increment afer the ingestion of glycoside patients, respectively, in the United States and India. Te solution [11]. Gastrointestinal adverse efects caused by high results showed a statistically signifcant reduction in HbA1c doses of D-tag suggest that this may act to reduce intestinal compared to the placebo group, concluding that it could glucose absorption. eventually become a treatment for diabetes [10]. In another randomized research [12] whose main objec- A cross, randomized, double-blind experimental design tive was to evaluate the safety and efect of D-tag on the determined the supplementation efect with tagatose on glycemic control in patients with DM 2 according to levels of postprandial hyperglycemia in 85 Korean hyperglycemic glycosylated hemoglobin (HbA1c) at the end of 6 months with individuals (�=52and �=33) [1] (Table 1). Blood samples diferent doses of D-tag, 2.5 g, 5.0 g, or 7.5g (3 times/day), were taken during fasting and afer drinking a beverage with controlling the serum level of blood glucose, plasma lipids, -erythritol (placebo) and other formulation with HbA1c, changes in body weight, and body mass index, as tagatose at 0, 30, 60, and 120 minutes, analyzing glucose, well as insulin variations [12], basal glycaemia dropped in insulin, C-peptide, and lipid profle [1]. Hyperglycemic indi- 3 and 6 months just in the group that received a dose of viduals of legal age had higher levels of triglycerides, Col- 7.5 g. Te average body weight dropped directly in greater total, LDL-Col, A1, and B apolipoprotein. Afer the intake of a proportion to doses of 5.0 g and 7.5 g of D-tag. Te minimum BioMed Research International 3

satiety, and insulin secretion [11]. In this sense, the capacity D-tag Glucose of tagatose to increase GLP-1 secretion is highly relevant to the lowering of blood glucose. D-tag is reported to stimulate GLP-1 to a comparable degree to fructose, whereas it did not stimulate GIP [11]. Because neither fructose nor tagatose is sodium-glucose cotransporter-1 (SGLT1) substrate, it follows that signaling pathways other than SGLT1 are likely to be Intestinal involved in GLP-1 secretion. Te exposure of poorly absorbed disaccharidases to the distal gut, with the production of short- chain fatty acids by bacterial fermentation, may represent an important mechanism of GLP-1 stimulation [14]. , a poorly absorbed , is a potent stimulus for GLP-1, andtagatosemayactinasimilarmanner,givenitsrelatively low absorption rate (∼25%). Wu et al. [15] showed that, in healthy humans, the preloads with tagatose/ Circulation (TIM),partiallyabsorbed,promotedaprolongedsecretion of GLP-1; this is probably stimulated by a long length in gut Figure 1: D-Tagatose glycemic control; proposed mechanism and therefore results in later GLP-1 secretion but does not explained that D-tagatose directly inhibits the absorption of glucose stimulate GIP.Nevertheless, GLP-1 was stimulated to a greater by intestinal disaccharidases. Note. Marion Guerrero-Wyss, Samuel level by the TIM than bythe sucralose preload immediately Duran´ Aguero,¨ Lisse Angarita Davila,´ 2017. afer the meal, and tagatose was also shown to slow gastric emptying rapidly [15], so that early gastrointestinal responses to tagatose might be mediated by other pathways, such as amount necessary to reduce the HbA1c corresponded to 5.0 g, GLUT5 (the fructose transporter) [15]. while the highest dose (7.5g) provided a greater efect on the On the other hand, a positive efect of D-tag in the evaluated parameters [12]. reduction of total cholesterol, VLDL, and LDL compared with sucrose has been reported [6]. Te proposed action 3.1. Proposed Mechanisms of the Metabolic Efect of D-Tag. mechanism may involve reduced pyruvate generation from It should be noted that the mechanisms related to the glycolysis, reducing acetyl CoA through the Krebs cycle efect of D-tagatose on the regulation of glycaemia are still as a precursor to cholesterol [13]. Some authors have also under study. However, some authors have described various described that D-tag has contributed to increasing levels mechanisms by which the antihyperglycemic efect of D- of HDL cholesterol [7]. Recently, it was suggested that D- tagatose could be explained, highlighting a direct inhibition tagatose blocks absorption of fructose through the gut and of intestinal disaccharidases, which would increase as the can efectively reduce diet-induced dyslipidemia [13]. period of intestinal exposure increases to D-tagatose (Fig- ure 1). 4. Toxicity of D-Tagatose Another proposed hypothesis could be explained through the inhibition of hepatic glycogenolysis [1] (Figure 2). A study was conducted to detect toxicity of D-tag in rats (SD) Tagatose seems to act by promoting synthesis and to [16], administering D-tag in three doses (4,000, 12,000, and decrease glycogen utilization. Sudhamani Muddada explains 20,000 mg/kg body weight/day) through gastric intubation that D-tag competitively inhibits the that metab- on days 6 to 15 of gestation period. Related toxicity or clinical olizes glycogen [13], causing glucose to remain stored as efects associated in maternal rats at a dose of 4000 mg/kg/day glycogen. On the other hand, it promotes the metabolism of were not observed. In the mid and high doses, nonformed glucose to glucose-6-P,which stimulates storage of glucose as stools were observed; this efect was more prominent in the glycogen. Te intermediate of tagatose metabolism tagatose- earlyperiodoftreatment(6thto8thday)attributedtothe 1-phosphate promotes the activity of , resulting in osmotic action of the big quantity administered of D-tag. increased phosphorylation of glucose to glucose-1-phosphate Tis molecule is not well digested or absorbed; most part of which activates glycogen synthase mobilising glucose to thesugargoestothecolon,whereitabsorbswaterandis glycogen. Tagatose-1-phosphate inhibits the activity of glyco- fermentedbycolonicbacteria.Tegroupsubmittedtothe gen phosphorylase preventing glycogen breakdown. It is highest dose experienced an average weight loss during the hypothesised that tagatose is metabolized like fructose but interval from the 6th to the 9th day of gestation, considered at a slower rate [13]. Also, tagatose prevents absorption of as a direct result of the laxative efect. In addition to this sucrose and by inhibiting the action of sucrases and action, the reduced consumption of food also contributed to maltases in the small intestine [1]. the decrease in weight gain. Animals exposed to medium and On the other hand, the interaction of ingested nutrients high dose presented one food intake less than the control with the small intestine to stimulate the release of gut pep- group. Adverse efects on reproductive performance were tides, including glucagon-like peptide 1 (GLP-1) and glucose- not observed in treatment groups or in the fetus overweight, dependent insulinotropic polypeptide (GIP), represents a neither in the distribution by sex, weight of the liver, nor major mechanism in the regulation of gastric emptying, external, visceral, or skeletal malformations in any dose [16]. 4 BioMed Research International

D-Tagatose D-Tagatose-1-P DHAP + GA ＃／2 +（2／ Aldolase B Metabolism of D- Similar to fructose-1-P, tagatose-1-P is tagatose in liver is an inhibitor of glycogen phosphorylase identical to that of fructose, but the Inhibition cleavage of tagatose-1-P occurs of only about half Promotion Glucose-1-P the rate of that fructose- Glucose-6-P 1-P Glycogen

Glycogen synthase phosphorylase Glucokinase Glycogen

Glucose-6-P produced by glucokinase promotes pathway action of the activation of hepatic glycogen synthase

Action

Pathway Figure 2: D-Tagatose glycemic control; proposed mechanism explained through the inhibition of hepatic glycogenolysis. Note.Adaptedfrom the original “Tagatose Glycemic Control MOA in the Liver” produced by Muddada, 2012 [13].

Te potential genotoxic efect of this molecule was exam- meal) per day for 8 weeks. Diabetics were assigned into two ined in fve standard trials [17]. In these tests, there was groups and received 75 g of D-tag or a supplement without not any signifcant increment in the ovary cells of Chinese sugar every day for 8 weeks. Tis test did not show a basal hamster with chromosomal alterations in concentrations up increment of uric acid in response to the daily intake of D- to 5000 mcg/ml with or without metabolic activation. It tag. However, a transient increase in the plasma level of uric was not found that D-tag could increase the frequency of acid was observed afer the single dose of 75 g of D-tag in the lymphoma cancer cells of mouse L5178Y with or without tolerance test at 60 minutes. In accordance with the previous metabolic activation; additionally, D-tag did not modify observations on the fructose, the increment of uric acid in micronucleus of polychromatic erythrocytes in the bone plasma was associated with a slight decrease of phosphorus in marrow, concluding that this molecule was not genotoxic in plasma and a slight increase of magnesium. Te daily intake thetrialsdescribedabove[17]. of D-tag for 8 weeks did not have any efect on the magnesium Another clinical, cross, and double-blind study evaluated in plasma in fasting, phosphorous, cholesterol, triglycerides, the efect of this against D-fructose on the HbA1c, glucose, and insulin. Ingestion of three doses of increment in the production of uric acid [18], through the 25 g/day for 8 weeks resulted in symptoms of fatulence in acceleration of purine nucleotide degradation as well as other seven of the eight individuals and some diarrhea in six metabolic parameters in 8 male individuals. It was detected individuals. Te authors concluded that D-tag is a promising that both the highest concentration of uric acid and the 4- sweetener without adverse efects observed in these trials. hour AUC were signifcantly higher afer the intake of D- Several studies were conducted to evaluate the gastroin- tag compared to 30 g D-fructose or water. It is concluded testinal symptoms in humans; these were analyzed afer the that D-tag attenuates glycemic and insulin response of a food consumptionof29or30gofD-tag[19].Nauseaanddiarrhea 255 minutes afer its ingestion. In addition, both sweeteners were reported with an incidence of 15.1 and 31.5%, respec- increased cholecystokinin (CCK) and peptide levels similar tively,in73healthyyoungmen.Teincreaseinfatulence to glucagon-1 (GLP-1). afer D-tagatose was frequently reported in all studies and did In the same two-phase investigation mentioned above not diminish over a period of 15 days with the intake of 30 g in [18]carriedoutin8healthyindividualsandin8individuals asingledosedaily.Inmostofthecases,moderatesymptoms with diabetes type 2, the efect of repeated doses of D-tag in were reported. However, the results suggest that the dose of urea, phosphorus, magnesium, lipids, and glycemic home- 30 g ingested at a specifc time can be superior to the dose that ostasis was determined. In the frst phase, 75 g of glucose should be recommended for ordinary use. wasadministeredandoraltoleranceofglucoseandD-tag Another study compared the efect of in the test was assessed. Uric acid, phosphorus, and magnesium form of sucrose and D-tag on the plasma concentrations of levels were determined in blood samples collected at 0, 30, cholesterol, hyperglycemia, and atherosclerosis [6]. Mice of 60,120,and180minutesafertheintake.Healthyindividuals both genders were fed with standard diet or a diet enriched received at random 75 g of D-tag or sucrose (25 g with each withsucroseorD-tagasasourceofcarbohydratesfor BioMed Research International 5

16 weeks; both diets contained equivalent amounts (g/kg) of product or food [24], these studies should be extended with of macronutrients. Te intake of food, body weight, and more frequency in patients with diabetes type 2 in order to diameter of adipocytes, concentration of cholesterol and compare diferences in the stability of the glycemic curve and serum lipoproteins, and aortic atherosclerosis were evaluated. get the value of these indicators in individuals with this type Immune-staining of macrophages and the contents of colla- of pathology [25, 26]. genintheaorticrootlesionswereexamined. Mice fed with D-tag showed similar intake of energy, 6. New Approaches in the Production and body weight, blood sugar, and insulin, but the group fed Biotechnology Usefulness of Tagatose with sucrose exhibited a higher energy intake, obesity, and hyperglycemia. Tere was an increment in the diameter Te potential applications of this monosaccharide in the of adipocytes, the levels of cholesterol and plasma triglyc- pharmaceutical industry and the agri-food market have erides, atherosclerosis, immune-staining in macrophages, reached a boom [27]. However, the use of D-tag is limited and reduction in collagen content compared to mice that by its high production cost [28]. Compared to the intracel- consumed D-tag and the control group. Tese results show lular , extracellular route is an interesting strategy that compared with sucrose the equivalent substitution of D- to increase the adequacy of biocatalysts [26]. Numerous tag as a carbohydrate in the diet does not lead to the same studies [28–31] have focused on this objective; recently a proportion of obesity, hyperglycemia, hyperlipidemia, and gene (TM0416) encoding protein D-tag 3-epimerase from atherosclerosis [6]. a hyperthermophile marine bacterium has been studied; A pilot study explored metabolic efects of D-tag [7] this metalloenzyme showed an unusual high activity for the administered orally at a dose of 15 g of D-tag 3 times a day epimerization of D-tag to D-, advance that could be with food, in individuals with diabetes type 2 for 12 months. functionally classifed in the production of unusual sugars None of the serious adverse efects were observed during [30]andanalternativetoproducevitaminC[28,30]. thetreatment;10outofthe12individualsrecruitedinitially Regarding its healthy prebiotic efect, it is known that the experienced gastrointestinal side efects that tended to be chemicalstructureoftagatosemustnotbealteredduring mild and transient. Average body weight decreased from the processing and storage of food [27]. In this regard, 108.4 kg to 103.3 kg (� = 0.001). HbA1c did not have a several studies have evaluated the thermal stability of this signifcant reduction; it went from 10.6% to 9.6% (� = 0.08). sweetener in milk and lemonade in diferent concentrations, HDL cholesterol levels increased progressively from a base concluding that this monosaccharide can be used in the for- level of 30.5 to 41.7 mg/dl in the 12 months in 6 individuals mulation of drinks for people with diabetes with a minimum who did not use lipid-modifying drugs during the study (�< chance of degradation and very low loss of prebiotic activity 0.001). In conclusion, D-tag improved body weight and HDL [32, 33]. cholesterol in this pilot study. Another recent investigation [34] highlighted the poten- Another trial [9] compared the efects of groups drug tial of the Lb. casei to reduce the accumulation of galactose (D-tag) and placebo (sucralose). Te dose of D-tag was 15 g in fermented milk by the metabolic pathway tagatose-6- dissolved in 125 to 250 ml of water three times a day (TD); the phosphate (T6-P) specifc for this species; this process, facing placebo dose was 1.5 g dissolved in 125 to 250 ml of water TD. the residual difculties caused by and galactose in Te authors concluded that D-tag was efective in reducing fermented dairy food, would be a potential alternative. Tese the level of HbA1c when it is administered for two months at wonderful advances in food technology make this molecule adoseof15gthreetimesadayjustbeforemeals[9]. an ideal sweetener in functional products for patients with diabetes [26, 32, 33], with the ability to positively afect the 5. Glycemic Index and Glycemic intestinal microbiota of these patients, making its consump- Load of Tagatose tion more interesting and useful in a little explored area [34– 42]. Several studies have shown a positive efect afer the intake of tagatose in healthy individuals [9–11, 20] resulting in a 7. Conclusion lowGI[20],comparedtoglucoseandwhitebreadasa reference food, glycemic index of D-tagatose was 3 and 4, Afer a decade of studies, tagatose became generally recog- respectively. While investigating the GI of other sweeteners nizedasasafeproducttobeusedinfoodandbeverages like maltitol (=26), xylitol (=8), or (=32) [21], it under FDA Regulation of Te United States. A subsequent is observed that D-tag has less value even when compared to trial that lasted 14 months confrmed its potential use to treat sweetener blends composed of polydextrose and sorbitol (=7) type 2 diabetes, showing great promise for inducing weight [20]. On the other hand, there is evidence of a null or very loss and increased cholesterol of high density lipoproteins, as low glycemic load GL (=0), compared to the value reported well as its importance for the control of diabetes. Tere are for maltitol (GL = 3), xylitol (=1), isomaltulose (=3), or the no current therapies for type 2 diabetes that provide these mixture of sorbitol and polydextrose (=1) [20]. It is known benefts. Several studies indicate that predominant side efects that the indicators of GI and GL should be done initially in of tagatose are gastrointestinal disorders only associated with healthy individuals to obtain a metabolic reference compared excessive consumption, efects that do not exceed a specifc with diabetic individuals [22]. Recognizing that the glycemic periodof2weeks,andthesehavebeenonlyobservedafer variability is very high [23] and specifc according to the type the consumption of high doses of tagatose. 6 BioMed Research International

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